Is EVC p.Thr295Ser (c.884C>G) pathogenic?

EVC p.Thr295Ser (c.884C>G) is classified Conflicting classifications of pathogenicity in EVC (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-01-31). AlphaMissense: likely benign (0.1326); Ultra-rare (popmax 0.0468%, eas); Associated with acrofacial dysostosis, Weyers type.

What condition is associated with EVC p.Thr295Ser (c.884C>G)?

EVC p.Thr295Ser (c.884C>G) is associated with acrofacial dysostosis, Weyers type, Ellis-van Creveld syndrome (ClinVar).

How common is EVC p.Thr295Ser (c.884C>G) in the general population?

EVC p.Thr295Ser (c.884C>G) is ultra-rare (popmax 0.0468%, eas) (gnomAD).

What do computational predictors say about EVC p.Thr295Ser (c.884C>G)?

AlphaMissense predicts likely benign (score 0.1326) — an in-silico prediction, not a clinical call.

EVC p.Thr295Ser

c.884C>G · rs754532508 · VCV557239

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1326 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0468%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

acrofacial dysostosis, Weyers type

Computational evidence

Protein change
AlphaMissense	0.1326	likely benign
REVEL	0.088	moderately benign-leaning
SaProt	LLR -5.53	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 2.7	GERP 0.036, phastCons 0.029
Regional constraint	o/e 1.12	unconstrained · MANE · 100 kb · p 1.2e-05 · regional, not allelic
Overall
CADD	9.354	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 · 21/44,868 alleles

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

Overall 0.0018% 29/1,613,740 alleles · ultra-rare exomes 25/1,461,574 · genomes 4/152,166 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0468%	2,137
Remaining individualsnot grpmax-eligible	0.0064%	15,625
South Asian	0.00329%	30,358
Admixed American	0.00167%	60,012

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: EVC
Protein: p.Thr295Ser
Coding: c.884C>G
MANE Select: NM_153717
dbSNP: rs754532508
Type: single nucleotide variant
Location: chr4:5745286 (GRCh38)
Gene constraint: LOEUF 1.134 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.49

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

Disease context

acrofacial dysostosis, Weyers type — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Ellis-van Creveld syndrome

Similar variants

EVC p.Thr295= Likely benign ★ same residue
EVC c.1098+1G>A Pathogenic/Likely pathogenic ★★ same condition
EVC c.175-2A>G Pathogenic/Likely pathogenic ★★ same condition
EVC c.1777-1G>A Pathogenic/Likely pathogenic ★★ same condition
EVC c.1777-2A>G Pathogenic/Likely pathogenic ★★ same condition
EVC c.1886+1G>C Likely pathogenic ★★ same condition
EVC c.1886+5G>A Pathogenic ★★ same condition
EVC c.1886+5G>T Pathogenic/Likely pathogenic ★★ 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/evc-p-thr295ser (accessed [today's date]).

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