Is SRCAP p.Leu1374Phe (c.4120C>T) pathogenic?

SRCAP p.Leu1374Phe (c.4120C>T) is classified Conflicting classifications of pathogenicity in SRCAP (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-01-27). AlphaMissense: likely benign (0.211); Ultra-rare (popmax 0.0172%, nfe); Associated with Floating-Harbor syndrome.

What condition is associated with SRCAP p.Leu1374Phe (c.4120C>T)?

SRCAP p.Leu1374Phe (c.4120C>T) is associated with Floating-Harbor syndrome, developmental delay, hypotonia, musculoskeletal defects, and behavioral abnormalities (ClinVar).

How common is SRCAP p.Leu1374Phe (c.4120C>T) in the general population?

SRCAP p.Leu1374Phe (c.4120C>T) is ultra-rare (popmax 0.0172%, nfe) (gnomAD).

What do computational predictors say about SRCAP p.Leu1374Phe (c.4120C>T)?

AlphaMissense predicts likely benign (score 0.211) — an in-silico prediction, not a clinical call.

SRCAP p.Leu1374Phe

c.4120C>T · rs777744269 · VCV598465

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.211 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0172%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Floating-Harbor syndrome

Computational evidence

Protein change
AlphaMissense	0.211	likely benign
REVEL	0.283	benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.3	GERP 1.5, phastCons 0.98
Regional constraint	o/e 1.03	unconstrained · MANE · 8,776 bp · p 0.24 · regional, not allelic
Overall
CADD	23.1	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0172% European (non-Finnish) · 203/1,179,842 alleles

Filtering AF 0.0152% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0145%

Overall 0.0134% 216/1,613,770 alleles · ultra-rare exomes 196/1,461,558 · genomes 20/152,212 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0172%	5,812
Remaining individualsnot grpmax-eligible	0.0096%	10,412
African / African-American	0.00534%	18,731
Admixed American	0.00333%	29,993
Finnishnot grpmax-eligible	0.00156%	64,038

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: SRCAP
Protein: p.Leu1374Phe
Coding: c.4120C>T
MANE Select: NM_006662
dbSNP: rs777744269
Type: single nucleotide variant
Location: chr16:30723190 (GRCh38)
Gene constraint: LOEUF 0.223 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 1374: a UniProt-annotated variant site (in dehmba)

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

Disease context

Floating-Harbor syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: developmental delay, hypotonia, musculoskeletal defects, and behavioral abnormalities

Similar variants

SRCAP p.Arg2329Ter Pathogenic/Likely pathogenic ★★ same condition
SRCAP p.Arg2435Ter Pathogenic/Likely pathogenic ★★ same condition
SRCAP p.Arg2444Ter Pathogenic ★★ same condition
SRCAP p.Arg2718Ter Pathogenic/Likely pathogenic ★★ same condition
SRCAP p.Arg2748Ter Pathogenic ★★ same condition
SRCAP p.Gln2407Ter Pathogenic ★★ same condition
SRCAP p.Gln2419Ter Pathogenic ★★ same condition
SRCAP p.Gln2665Ter 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/srcap-p-leu1374phe (accessed [today's date]).

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