Is EGFLAM p.Asn953Ser (c.2858A>G) pathogenic?

EGFLAM p.Asn953Ser (c.2858A>G) is classified Uncertain significance in EGFLAM (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-12). AlphaMissense: likely benign (0.0628); Ultra-rare (popmax 0.0966%, sas).

How common is EGFLAM p.Asn953Ser (c.2858A>G) in the general population?

EGFLAM p.Asn953Ser (c.2858A>G) is ultra-rare (popmax 0.0966%, sas) (gnomAD).

What do computational predictors say about EGFLAM p.Asn953Ser (c.2858A>G)?

AlphaMissense predicts likely benign (score 0.0628) — an in-silico prediction, not a clinical call.

EGFLAM p.Asn953Ser

c.2858A>G · rs761267268 · VCV3087671

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0628 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0966%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.0628	likely benign
REVEL	0.388	indeterminate
SaProt	LLR -6.16	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.1	GERP -0.99, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 205 kb · p 0.46 · regional, not allelic
Overall
CADD	23.3	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM N961S vs ClinVar N953S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0966% South Asian · 88/91,074 alleles

Filtering AF 0.0803% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0743%

Overall 0.00973% 157/1,614,028 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0966%	1,035
East Asian	0.0245%	4,080
Admixed American	0.0117%	8,574
Remaining individualsnot grpmax-eligible	0.0048%	20,830
European (non-Finnish)	0.0039%	25,651
African / African-American	0.00267%	37,516

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: EGFLAM
Protein: p.Asn953Ser
Coding: c.2858A>G
MANE Select: NM_152403
dbSNP: rs761267268
Type: single nucleotide variant
Location: chr5:38462994 (GRCh38)
Gene constraint: LOEUF 0.83 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.81 · 3 PDB
Residue 953: a β-strand; the laminin g-like 3 domain

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

Similar variants

EGFLAM p.Asn953Asp Uncertain significance ★ ⚠ same residue
EGFLAM p.Asn913= Benign ★★ same type
EGFLAM p.Trp229Arg Benign ★★ same type
EGFLAM c.2465-2611T>C Uncertain significance ★ ⚠ same type
EGFLAM p.Ala115Val Uncertain significance ★ ⚠ same type
EGFLAM p.Ala143Pro Uncertain significance ★ ⚠ same type
EGFLAM p.Ala314Thr Uncertain significance ★ ⚠ same type
EGFLAM p.Ala45Thr 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/egflam-p-asn953ser (accessed [today's date]).

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