Is SEMA4A p.Pro95Ala (c.283C>G) pathogenic?

SEMA4A p.Pro95Ala (c.283C>G) is classified Uncertain significance in SEMA4A (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-27). AlphaMissense: likely benign (0.1828); Ultra-rare (popmax 0.0166%, mid).

How common is SEMA4A p.Pro95Ala (c.283C>G) in the general population?

SEMA4A p.Pro95Ala (c.283C>G) is ultra-rare (popmax 0.0166%, mid) (gnomAD).

What do computational predictors say about SEMA4A p.Pro95Ala (c.283C>G)?

AlphaMissense predicts likely benign (score 0.1828) — an in-silico prediction, not a clinical call.

SEMA4A p.Pro95Ala

c.283C>G · rs774683776 · VCV1508934

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1828 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0166%, mid)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1828	likely benign
REVEL	0.093	moderately benign-leaning
SaProt	LLR -10.18	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.7	GERP 2, phastCons 0.99
Regional constraint	o/e 0.96	unconstrained · MANE · 22 kb · p 0.28 · regional, not allelic
Overall
CADD	14.79	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 0.0166% Middle Eastern · 1/6,028 alleles

Overall 0.000124% 2/1,613,914 alleles · ultra-rare exomes 2/1,461,766 · genomes 0/152,148 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0166%	6,028
European (non-Finnish)	8.47e-05%	1,179,970

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.Pro95Ala
Coding: c.283C>G
MANE Select: NM_022367
dbSNP: rs774683776
Type: single nucleotide variant
Location: chr1:156156557 (GRCh38)
Gene constraint: LOEUF 0.858 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.05
Residue 95: the sema domain

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

Similar variants

SEMA4A c.*208A>G Uncertain significance ★★ same type
SEMA4A p.Ala114Thr Uncertain significance ★★ ⚠ same type
SEMA4A p.Ala181Thr Uncertain significance ★★ ⚠ same type
SEMA4A p.Ala337Val Uncertain significance ★★ same type
SEMA4A p.Ala446Val Uncertain significance ★★ ⚠ same type
SEMA4A p.Ala509Gly Uncertain significance ★★ ⚠ same type
SEMA4A p.Ala570Thr Uncertain significance ★★ ⚠ same type
SEMA4A p.Ala585Ser Uncertain significance ★★ ⚠ same type

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-pro95ala (accessed [today's date]).

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