Is AWAT2 p.Arg77Ser (c.229C>A) pathogenic?

AWAT2 p.Arg77Ser (c.229C>A) is classified Uncertain significance in AWAT2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-27). AlphaMissense: likely benign (0.1559); Very rare (popmax 0.00447%, amr).

How common is AWAT2 p.Arg77Ser (c.229C>A) in the general population?

AWAT2 p.Arg77Ser (c.229C>A) is very rare (popmax 0.00447%, amr) (gnomAD).

What do computational predictors say about AWAT2 p.Arg77Ser (c.229C>A)?

AlphaMissense predicts likely benign (score 0.1559) — an in-silico prediction, not a clinical call.

AWAT2 p.Arg77Ser

c.229C>A · VCV3812874

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1559 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00447%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1559	likely benign
REVEL	0.044	moderately benign-leaning
SaProt	LLR -3.88	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 -3.5	GERP -4.1
Regional constraint	o/e 0.82	unconstrained · MANE · 8,121 bp · p 0.0027 · regional, not allelic
Overall
CADD	0.002	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00447% Admixed American · 2/44,778 alleles

Filtering AF 0.00074% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000345%

Overall 0.000917% 11/1,199,369 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00447%	22,389
European (non-Finnish)	0.00101%	98,866

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: AWAT2
Protein: p.Arg77Ser
Coding: c.229C>A
MANE Select: NM_001002254
Type: single nucleotide variant
Location: chrX:70043964 (GRCh38)
Structure: AlphaFold pLDDT 94.34

Full AWAT2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

AWAT2 p.Ala12Ser Uncertain significance ★ ⚠ same type
AWAT2 p.Ala159Ser Uncertain significance ★ ⚠ same type
AWAT2 p.Arg191Ser Uncertain significance ★ ⚠ same type
AWAT2 p.Arg205Gln Uncertain significance ★ ⚠ same type
AWAT2 p.Arg205Trp Uncertain significance ★ ⚠ same type
AWAT2 p.Arg244His Uncertain significance ★ ⚠ same type
AWAT2 p.Arg65Gln Uncertain significance ★ ⚠ same type
AWAT2 p.Arg68Cys 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/awat2-p-arg77ser (accessed [today's date]).

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