Is EVC p.Ser665Leu (c.1994C>T) pathogenic?

EVC p.Ser665Leu (c.1994C>T) is classified Uncertain significance in EVC (ClinVar, Single submitter, 1 submitter; last evaluated 2018-01-13). AlphaMissense: likely benign (0.1457); Ultra-rare (popmax 0.011%, sas); Associated with Ellis-van Creveld syndrome.

What condition is associated with EVC p.Ser665Leu (c.1994C>T)?

EVC p.Ser665Leu (c.1994C>T) is associated with Ellis-van Creveld syndrome (ClinVar).

How common is EVC p.Ser665Leu (c.1994C>T) in the general population?

EVC p.Ser665Leu (c.1994C>T) is ultra-rare (popmax 0.011%, sas) (gnomAD).

What do computational predictors say about EVC p.Ser665Leu (c.1994C>T)?

AlphaMissense predicts likely benign (score 0.1457) — an in-silico prediction, not a clinical call.

EVC p.Ser665Leu

c.1994C>T · rs375340438 · VCV904457

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1457 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.011%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Ellis-van Creveld syndrome

Computational evidence

Protein change
AlphaMissense	0.1457	likely benign
REVEL	0.224	benign-leaning
SaProt	LLR -5.67	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 2.1	GERP 1.8, phastCons 0.97
Regional constraint	o/e 1.12	unconstrained · MANE · 100 kb · p 1.2e-05 · regional, not allelic
Overall
CADD	22.0	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 0.011% South Asian · 10/91,080 alleles

Filtering AF 0.00594% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00453%

Overall 0.00112% 18/1,613,578 alleles · ultra-rare exomes 18/1,461,242 · genomes 0/152,336 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.011%	9,108
Remaining individualsnot grpmax-eligible	0.0032%	31,250
African / African-American	0.00133%	75,066
European (non-Finnish)	0.000424%	236,002

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.Ser665Leu
Coding: c.1994C>T
MANE Select: NM_153717
dbSNP: rs375340438
Type: single nucleotide variant
Location: chr4:5797129 (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

Ellis-van Creveld syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

EVC p.Ser665= 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-ser665leu (accessed [today's date]).

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