Is SEMA4A p.Pro682Ser (c.2044C>T) pathogenic?

SEMA4A p.Pro682Ser (c.2044C>T) is classified Benign/Likely benign in SEMA4A (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-02-01). AlphaMissense: likely benign (0.1172); Low-frequency (popmax 1.98%, nfe); Associated with retinitis pigmentosa.

What condition is associated with SEMA4A p.Pro682Ser (c.2044C>T)?

SEMA4A p.Pro682Ser (c.2044C>T) is associated with retinitis pigmentosa, retinitis pigmentosa 35, cone-rod dystrophy 10 (ClinVar).

How common is SEMA4A p.Pro682Ser (c.2044C>T) in the general population?

SEMA4A p.Pro682Ser (c.2044C>T) is low-frequency (popmax 1.98%, nfe) (gnomAD).

How is Retinitis pigmentosa inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about SEMA4A p.Pro682Ser (c.2044C>T)?

AlphaMissense predicts likely benign (score 0.1172) — an in-silico prediction, not a clinical call.

SEMA4A p.Pro682Ser

c.2044C>T · rs76381440 · VCV286515

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.1172 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.98%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

retinitis pigmentosa

Computational evidence

Protein change
AlphaMissense	0.1172	likely benign
REVEL	0.208	benign-leaning
SaProt	LLR -7.72	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.7	GERP 2.1, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 22 kb · p 0.28 · regional, not allelic
Overall
CADD	19.59	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.98% European (non-Finnish) · 23,283/1,178,540 alleles

Filtering AF 1.95% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.95%

Overall 1.61% 25,916/1,612,332 alleles · low-frequency exomes 24,333/1,459,994 · genomes 1,583/152,338 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	1.98%	51
Remaining individualsnot grpmax-eligible	1.52%	66
Admixed American	0.745%	134
South Asian	0.604%	166
Finnishnot grpmax-eligible	0.472%	212
Ashkenazi Jewishnot grpmax-eligible	0.45%	222
Amishnot grpmax-eligible	0.439%	228
African / African-American	0.309%	323
Middle Eastern	0.248%	404

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: SEMA4A
Protein: p.Pro682Ser
Coding: c.2044C>T
MANE Select: NM_022367
dbSNP: rs76381440
Type: single nucleotide variant
Location: chr1:156176755 (GRCh38)
Gene constraint: LOEUF 0.858 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.05

Full SEMA4A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

retinitis pigmentosa — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: retinitis pigmentosa 35 cone-rod dystrophy 10

For Retinitis pigmentosa (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, Mitochondrial inheritance
Onset: Adolescent, Adult, Childhood
Prevalence: 1-5 / 10 000 (Europe)

Similar variants

SEMA4A c.*208A>G Uncertain significance ★★ same condition
SEMA4A p.Ala446Val Uncertain significance ★★ ⚠ same condition
SEMA4A p.Ala751Thr Uncertain significance ★★ ⚠ same condition
SEMA4A p.Ala83Pro Uncertain significance ★★ ⚠ same condition
SEMA4A p.Arg375Trp Uncertain significance ★★ ⚠ same condition
SEMA4A p.Arg494Gln Uncertain significance ★★ ⚠ same condition
SEMA4A p.Arg557Trp Uncertain significance ★★ ⚠ same condition
SEMA4A p.Arg711Trp Uncertain significance ★★ ⚠ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/sema4a-p-pro682ser (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown