Is C8A p.Ala35Thr (c.103G>A) pathogenic?

C8A p.Ala35Thr (c.103G>A) is classified Conflicting classifications of pathogenicity in C8A (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-01-06). AlphaMissense: likely benign (0.0639); Ultra-rare (popmax 0.0468%, eas).

How common is C8A p.Ala35Thr (c.103G>A) in the general population?

C8A p.Ala35Thr (c.103G>A) is ultra-rare (popmax 0.0468%, eas) (gnomAD).

What do computational predictors say about C8A p.Ala35Thr (c.103G>A)?

AlphaMissense predicts likely benign (score 0.0639) — an in-silico prediction, not a clinical call.

C8A p.Ala35Thr

c.103G>A · rs201034819 · VCV2063157

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0639 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0468%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0639	likely benign
REVEL	0.123	moderately benign-leaning
SaProt	LLR -5.88	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 -2.4	GERP -4.3
Regional constraint	o/e 1.08	unconstrained · MANE · 63 kb · p 0.034 · regional, not allelic
Overall
CADD	0.045	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 0.0468% East Asian · 21/44,846 alleles

Filtering AF 0.0313% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0263%

Overall 0.00502% 81/1,613,656 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0468%	2,136
African / African-American	0.00667%	14,997
Remaining individualsnot grpmax-eligible	0.0064%	15,622
European (non-Finnish)	0.00398%	25,102
Admixed American	0.00334%	29,975
Finnishnot grpmax-eligible	0.00156%	63,992
South Asian	0.0011%	91,054

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: C8A
Protein: p.Ala35Thr
Coding: c.103G>A
MANE Select: NM_000562
dbSNP: rs201034819
Type: single nucleotide variant
Location: chr1:56867634 (GRCh38)
Gene constraint: LOEUF 1.168 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.58 · 11 PDB
Residue 35: an α-helix

Full C8A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

C8A p.Arg424Ter Pathogenic ★★ same type
C8A p.Arg498Ter Pathogenic/Likely pathogenic ★★ same type
C8A p.Glu466Ter Pathogenic ★★ same type
C8A p.Tyr210Ter Pathogenic/Likely pathogenic ★★ same type
C8A p.Tyr384Ter Pathogenic/Likely pathogenic ★★ same type
C8A p.Arg107Cys Uncertain significance ★★ ⚠ same type
C8A p.Arg196His Uncertain significance ★★ ⚠ same type
C8A p.Arg207Gln 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/c8a-p-ala35thr (accessed [today's date]).

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